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Talin activates integrins by altering the topology of the ? transmembrane domain.

ABSTRACT: Talin binding to integrin ? tails increases ligand binding affinity (activation). Changes in ? transmembrane domain (TMD) topology that disrupt ?-? TMD interactions are proposed to mediate integrin activation. In this paper, we used membrane-embedded integrin ?3 TMDs bearing environmentally sensitive fluorophores at inner or outer membrane water interfaces to monitor talin-induced ?3 TMD motion in model membranes. Talin binding to the ?3 cytoplasmic domain increased amino acid side chain embedding at the inner and outer borders of the ?3 TMD, indicating altered topology of the ?3 TMD. Talin's capacity to effect this change depended on its ability to bind to both the integrin ? tail and the membrane. Introduction of a flexible hinge at the midpoint of the ?3 TMD decoupled the talin-induced change in intracellular TMD topology from the extracellular side and blocked talin-induced activation of integrin ?IIb?3. Thus, we show that talin binding to the integrin ? TMD alters the topology of the TMD, resulting in integrin activation.

SUBMITTER: Kim C

PROVIDER: S-EPMC3365499 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Talin activates integrins by altering the topology of the β transmembrane domain.

Kim Chungho C Ye Feng F Hu Xiaohui X Ginsberg Mark H MH

The Journal of cell biology 20120501 5

Talin binding to integrin β tails increases ligand binding affinity (activation). Changes in β transmembrane domain (TMD) topology that disrupt α-β TMD interactions are proposed to mediate integrin activation. In this paper, we used membrane-embedded integrin β3 TMDs bearing environmentally sensitive fluorophores at inner or outer membrane water interfaces to monitor talin-induced β3 TMD motion in model membranes. Talin binding to the β3 cytoplasmic domain increased amino acid side chain embeddi ...[more]

PMID: 22641344

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Project description:Key pointsThe electrogenic Na+ /HCO3 - cotransporter NBCe1-B is widely expressed in many tissues, including pancreas, submandibular gland, brain, heart, etc. NBCe1-B has very low activity under basal condition due to auto-inhibition, but can be fully activated by protein interaction with the IP3R-binding protein released with inositol 1,4,5-trisphosphate (IRBIT). The structural components of the auto-inhibition domain and the IRBIT-binding domain of NBCe1-B are finely characterized based on systematic mutations in the present study and data from previous studies. Reducing negative charges on the cytosol side of the transmembrane domain greatly decreases the magnitude of the auto-inhibition of NBCe1-B. We propose that the auto-inhibition domain functions as a brake module that inactivates NBCe1-B by binding to, via electrostatic attraction, the transmembrane domain; IRBIT activates NBCe1-B by releasing the brake from the transmembrane domain via competitive binding to the auto-inhibition domain.AbstractThe electrogenic Na+ /HCO3 - cotransporter NBCe1-B is widely expressed in many tissues in the body. NBCe1-B exhibits only basal activity due to the action of the auto-inhibition domain (AID) in its unique amino-terminus. However, NBCe1-B can be activated by interaction with the IP3R-binding protein released with inositol 1,4,5-trisphosphate (IRBIT). Here, we investigate the molecular mechanism underlying the auto-inhibition of NBCe1-B and its activation by IRBIT. The IRBIT-binding domain (IBD) of NBCe1-B spans residues 1-52, essentially consisting of two arms, one negatively charged (residues 1-24) and the other positively charged (residues 40-52). The AID mainly spans residues 40-85, overlapping with the IBD in the positively charged arm. The magnitude of auto-inhibition of NBCe1-B is greatly decreased by manipulating the positively charged residues in the AID or by replacing a set of negatively charged residues with neutral ones in the transmembrane domain. The interaction between IRBIT and NBCe1-B is abolished by mutating a set of negatively charged Asp/Glu residues (to Asn/Gln) plus a set of Ser/Thr residues (to Ala) in the PEST domain of IRBIT. However, this interaction is not affected by replacing the same set of Ser/Thr residues in the PEST domain with Asp. We propose that: (1) the AID, acting as a brake, binds to the transmembrane domain via electrostatic interaction to slow down NBCe1-B; (2) IRBIT activates NBCe1-B by releasing the brake from the transmembrane domain.

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Talin activates integrins by altering the topology of the ? transmembrane domain.

Publications

Talin activates integrins by altering the topology of the β transmembrane domain.

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